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Eur J Cardiothorac Surg 2007;31:383-390. doi:10.1016/j.ejcts.2006.11.048
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

In vivo h-VEGF₁₆₅ gene transfer improves early endothelialisation and patency in synthetic vascular grafts

^a Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden
^b Department of Clinical Chemistry, Uppsala University Hospital, Sweden
^c Clinical Research Center, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden
^d Department of Cardiothoracic Surgery, Southampton University Hospitals, Southampton, UK
^e Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
^f Statistical Consulting Center, Wright State University, Dayton, OH, USA

Received 20 March 2006; received in revised form 12 September 2006; accepted 22 November 2006.

^_* Corresponding author. Address: Department of Clinical Chemistry, Entrance 61, 3rd floor, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel.: +46 708 901090; fax: +46 18 6113703. (Email: mika.lahtinen{at}medsci.uu.se).

Objectives: Small-diameter synthetic vascular graft performance is inferior to autologous vein grafts. This study tested the hypotheses that local in vivo administration of plasmids encoding for human vascular endothelial growth factor (VEGF), or co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2 in the tissues surrounding a porous synthetic vascular graft would enhance graft endothelialisation and, consecutively, graft patency. Methods: First, optimal gene for small-diameter synthetic graft endothelialisation was studied in rat abdominal aorta model (n = 132): plasmids encoding for human vascular endothelial growth factor; co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2; or control plasmids were injected around 60 µm ePTFE graft. Second, optimal small-diameter synthetic graft design for endothelialisation was explored in rabbit abdominal aorta model (n = 90). Various ePTFE grafts or pre-clotted polyester grafts were used with/without plasmids encoding for human vascular endothelial growth factor. Third, clinically used medium-size synthetic grafts were investigated with/without plasmids encoding for human vascular endothelial growth factor in dog carotid (n = 20) and femoral arteries (n = 15). Endothelialisation was assessed in midgraft area with scanning electron microscopy. Results: In rats, plasmids encoding for human vascular endothelial growth factor enhanced endothelialisation; whereas co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2 had worst outcome at 1 week (NS), 2 weeks (P = 0.01) and 4 weeks (P = 0.02). In rabbits, pre-clotted polyester grafts had a trend for faster endothelialisation than ePTFE grafts (P = 0.08); whereas plasmids encoding for human vascular endothelial growth factor enhanced endothelialisation compared to controls at 2 weeks (P = 0.06), however, the effect reversed at 4 weeks (P = 0.03). In dogs, synthetic graft patency was improved by plasmids encoding for human vascular endothelial growth factor in femoral position (P = 0.103); whereas all carotid grafts were patent at 6 weeks. Conclusions: Thus, these data suggested that endothelialisation was fastest in pre-clotted polyester grafts; and that local application of plasmids encoding for human vascular endothelial growth factor had a potential to improve early endothelialisation and patency in synthetic vascular grafts.

Key Words: Angiogenesis • Endothelium • Gene therapy • Patency • Prosthesis • VEGF